Depression Is Not A Proton and Other Nosological Musings....

 

I have been thinking about protons a lot lately. Probably not too unusual for an old science guy.  After all we used them in chemistry and physics.  I have been doing some reading about stellar evolution lately and how the elements were formed. In that reading I came across the fact that a proton has a life of 10^32 years. Some estimates say 10^34 years.  And proton decay doesn’t happen slowly over time. At some point it is just instantaneous.  A proton is a composite particle rather than an elementary particle – composed of three valence quarks resulting in a net positive charge. But in chemistry and biochemistry they are generally written as a simple H⁺.  When protons decay – it happens instantaneously to a positron and a pion.  The positron is antimatter so it collides with an electron and is annihilated and gives off gamma photons.  The pion explodes doing the same.  The proton is converted to energy. This process is so rare it has never been directly observed although there is a massive experiment in progress to see if it can be done.

Practically all the protons in the universe today, were made during the Big Bang about 13.8 billion years ago.  Some protons are made in the universe today but it is a very small process compared with the original source. That means that all of the protons in my body (and yours) are recycled and will be for the next 10^23 years.  That’s nearly a trillion trillion (10^24) years.  The various estimates for the death of the universe range from tens of billions of years to 10^100 years.  And of course, life on Earth and Earth as a habitable planet is much shorter.

All of these thoughts about protons brings to mind Carl Sagan’s various quotes about how we are all made of stardust.  His thoughts go far beyond protons to every element in our bodies and how they were synthesized in stars and temporarily borrowed by us. Each one of us is an aggregate of this star dust maintained by energy input and localization. Part of Sagan’s intent was to point out how this can be reassuring and spiritual.  I do find it that way.

There is something else about protons. The verbal description of protons may vary slightly between disciplines (physics, particle physics, chemistry, biochemistry) but everyone is in agreement that protons exist and can see the logic of all of the notations and definitions.  Everyone agrees that there is one type of proton and it will be around forever.

A lot of people will say species are qualitatively different from disease and protons are qualitatively different from organisms and diseases.  Without using any philosophical words – species, protons, and diseases have different rules of existence, boundaries, and causal mechanisms.  To cite one example – no biological organism or disease originated in the Big Bang and is expected to last forever. The rules of existence are much different for a proton. It also does not adapt, process information, or experience or feel anything.  An organism has emergent rather than summed properties, is subject to evolutionary pressure, complex organization, and a finite lifespan. At the basic level the proton is a thing and an organism is a process over time – a qualitative difference.

The comparison of species to disease shows that species are generally individuals and diseases are abstract classes.  The individuals are organized in an evolutionary or phylogenic classification and diseases are organized as a disruption of normal physiological or mental function in an individual.  The species move through time and the disease happens to an individual at one point in time. As the appreciation of disease complexity has increased over time there is now an understanding that the lines that blur the distinction between species can also occur with diseases. 

That obviously is the case in biology and medicine. From taxonomy, we can find rare cases of organisms that are the only match to their phenotype – there is one description of a single genus and species.  We can also find identical phenotypes that can be separated into genus and species only by genetic subtyping. We can find monogenic diseases that produce several phenotypes and polygenic diseases that produce many more. In other words – the match between description and consensus-based reality is far from perfect.

I attempted to capture this phenomenon in the diagram at the top of this post.  I eschew the idea of a spectrum or continuum, the categories are presented here just to give estimates of possible numbers of subtypes in each category and the associated uncertainty. Some may take issue with including speciation with diseases.  In that case I will defer to Linnaeus who classified both and invented the predominant classification nomenclature still used in taxonomy.  

To be clear – this graphic is literally an apple to oranges comparison.  The first issue is the physical wave-particle compared to biological entities.  The second is the different levels within biology.  Species occur at the population level over time defined by properties such as reproductive isolation, morphological distinguishability, and monophyly.  The boundaries between species reflect evolutionary divergence rather than trait variation.  

To cite few examples moving from left to right. The proton is off the chart because there is no discrepancy between description and there is only one agreed upon type.  The first three organisms (Gingko biloba, Balaeniceps rex, and Thermus aquaticus) all have just one species through evolutionary mechanisms.  I did not equate them to a proton because being trained in biology (and without looking it up) – I am sure there are various descriptions but common recognition they are the same species.

Things get interesting with the Bornean Fanged Frog.  In this case all of the frogs look exactly alike and can only be separated into 18 different species by molecular genetics (1).  The authors specific quote “single species has been split into 18 genetically divergent yet morphologically indistinguishable species.”  This is the definition of a cryptic species but they also point out controversy about that definition and say that cryptic species are common in the Tree of Life and understanding them is critical to understanding biodiversity. 

Moving on to monogenic diseases, most of which can be identified by molecular tests there are also limited number of phenotypes that do not add much to classification but can be important in terms of treatment. Infection and toxic agents are generally thought of as being defined by the agent involved but there are a number of possible phenotypes based on host susceptibility, organ system involved, disease state, lethality of the infection agent or toxin, and in the case of the latter – toxidromes. 

That brings me to major depression – one of the most maligned diagnostic criteria in the DSM.  When I read the critiques, it seems like some people believe there will be a magical verbal description of depression and all of our worries will be over.  The sun will shine and we will never have to worry about actually treating the vagaries of depression on a clinical basis. The new pure description will be perfect enough to lead to an improvement in biological research and therapeutics.  The other more insidious part of that criticism is “I know more about depression than anybody and this is how it should be classified and diagnosed.” 

I don’t buy that criticism.  And here is why – I have seen tens of thousands of people with severe depression and bipolar disorder successfully treated during the eras of the DSM-III, DSM-IV, and DSM-5 and have worked with the thoughtful experts involved.  I don’t think for a second that it matters what was in those manuals or what turns up in the DSM-6.  Assessing and treating depression and differentiating it from other conditions doesn’t depend on what is in the DSM or the ICD.  It depends on what is in the mind of the psychiatrist, how that mind was trained, and what that mind experienced. 

As far as the classification goes – I can show the table of contents of Kraepelin’s text Clinical Psychiatry (2) to any practicing psychiatrist today and they will recognize what he is talking about over a hundred years ago.  It seems that we have to deny the validity of previous observations or label them as “pragmatic” but otherwise meaningless. The newer hierarchical or network-based schemes don’t mention the circularity of being based on descriptions pulled directly out of the DSM and all previous observations.

The diagram shows that based on the DSM criteria there are 227 possible phenotypes of varying frequency and a recent study showed that only 170 were observed in a large clinical sample.  Genomic studies often use a compromised phenotype by using the PHQ-9 or PHQ-2.  Nobody ever suggests that is a “practical” research compromise when you are analyzing the genomes of many more people than several psychiatrists would see in their lifetime.  But that is one reason some people think we need better criteria. How will better criteria be useful in rapidly characterizing 100,000 people for a genomics study?  Let me go out on a limb here and say there will be no better verbal or written criteria.  There is a limit of what you can classify with just words – especially in biology.

The proof is evident in the next three categories.  Everyone can recognize a domestic dog. There is tremendous phenotypic diversity in dogs based on morphology and behavior.  And they are all the same genus and species. Atopic dermatitis or eczema is one of the most common dermatological conditions and based on IgE status, age at onset, course, endotype, molecular endotype, chronicity, fillagrin mutation status, and severity there are 6,144 combinations although there is clinical overlap and there has been no clinical investigation into how many of those variants exist. From a morphological standpoint - many different rashes from eczema can exist on the same person at the same time and specialists in dermatology are the best people to diagnose that.  The same analysis can be done for systemic lupus erythematosus (SLE) using formal criteria and that produces 27,648 combinations of signs, symptoms, and lab findings.        

There is a range to the limits of verbal classification in biology and medicine.  In the case of cryptic species, we have a phenotype that presents very little perceptual or verbal information for classification and that classification depends on molecular biology.  In some cases, there is a one-to-one mapping of classification onto species.  That rarely if ever works in medicine and examples abound. I would not expect it to happen at high rates in biological organisms with stochastic processes, genetic mechanisms like incomplete penetrance, variable expressivity, polygenic modification of monogenic risk, epistasis, pleiotropy, allelic heterogeneity, epigenetic variability, and compound inheritance all increasing the gap between genotypes and expected phenotypes.  Approximate classifications are not a deterrent to science or clinical practice even though that is a common critical opinion. 

Stay tuned for an even deeper dive into biological classification of diseases based on some of these concepts. 

 

George Dawson, MD, DFAPA

 

References:

1:  Kin Onn Chan, Dario N Neokleous, Shahrul Anuar, Rafe M Brown, Carl R Hutter, Indraneil Das, Stefan T Hertwig, A Genomic Perspective on Cryptic Species Reveals Complex Evolutionary Dynamics in the Gray Zone of the Speciation Continuum, Systematic Biology, 2026;, syag001, https://doi.org/10.1093/sysbio/syag001 (open access).

2:  Kraepelin E.  Clinical Psychiatry.  The MacMillan Company/Norwood Press, Norwood,MA 1902, 1907. 628 p.

3:  Kendler KS. The Phenomenology of Major Depression and the Representativeness and Nature of DSM Criteria. Am J Psychiatry. 2016 Aug 1;173(8):771-80. doi: 10.1176/appi.ajp.2016.15121509. Epub 2016 May 3. PMID: 27138588.

4:  Zachar P, Kendler KS. The Philosophy of Nosology. Annu Rev Clin Psychol. 2017 May 8;13:49-71. doi: 10.1146/annurev-clinpsy-032816-045020. PMID: 28482691.

Graphics Credit:

An original from me - generated with MS Visio.

Phenotypic diversity from dogs to diseases

 

Whether you are trying to keep your neighbor’s German shepherd out of your yard or avoiding that biting Chihuahua on your way to the mail boxes – people have no problem identifying domestic dogs. Most can tell they are not foxes, wolves, or coyotes. There are approximately 400 different domestic dog breeds worldwide – but they all have the same taxonomic classification.

All domestic dogs belong to the same genus and species according to Linnean classification and that is Canis familiarus.  The genus was established in 1758 by Linnaeus to include dogs, wolves (C. rufus, C. lycaon, C. lupus, C. lupaster, C. simnesis) , coyotes (C. latrans), and jackals (C. aureus).  Foxes belong to the genus Vulpes and there are 12 species. This genus forms a clade meaning that they are all descended from a common ancestor.

Domestic dogs can be traced back to 15,000 to 100,000 years ago when they were originally descended from the Gray Wolf in East Asia (1).  Breeding programs have been used to select specific physical and behavioral characteristics of domestic dogs that had led to the observed phenotypic diversity.  The domestication process in general has selected for genetic changes and associated changes at the neurobiological level.  High prevalence illnesses are observed in some dog breeds suggesting that there are heritable loci that could be studied and provide some guidance for human diseases.  Purebred dogs can also have extensive genealogies including family histories and pathology data. 

In terms of comparative genomics (1) there are 4 clades of placental mammals  Afrotheria: ( elephants, manatees, and hyraxes), Xenartha: (sloths, anteaters, and armadillos),  Euarchontoglires: Euarchonta (primates, tree shrews, colugos) + Glires (rodents and lagomorphs), and Laurasiatheria: (shrews, hedgehogs, bats, and other carnivores including dogs).  The most extensively studied mammals at the genetic level all belong to Euarchontoglires (human, chimpanzee, mouse, rat). More detailed information on the dog genome allows for analysis for sections of conserved human DNA, reconstruction of the genetics of a common ancestor between clades, and investigations into the nature of polygenically determined illnesses.

One of the most interesting aspects of reference 1 is the phylogenic tree of the family Canidae showing the relationships between different phyla. This tree was constructed looking at 12 exons (8,080 base pairs (bp) and 4 introns (3029 bp). They were sequences in 30 of the 34 Canid species.  Note where domestic dogs are on the diagram. The boxer photo is used because the boxer genome was the prototypical analysis in this paper because it has some of the longest stretches of homozygosity (62%).  In the diagram clades are color coded (see legend). Each cladogram is constructed with Bayesian analysis generating the respective bootstrap values from Markov chain analysis and posterior probabilities (see legend for location). Indels are insertions-deletions.  Divergence times are in millions of years and are applied to the wolf-like clade discussed in the paper (color coded blue).   

The authors constructed a map of 2,559,519 SNPs (single nucleotide polymorphisms).  They were able to determine the SNP rate for domestic dog breeds and other Canids (wolves and coyotes) and determined it was essentially 1 SNP per 900 (bp) base pairs for all the dog breeds studied except the Alaskan malemute (~1/790 bp).  Wolves and coyotes had greater variation than dogs suggesting a bottleneck during dog domestication.   The authors also demonstrated limited haplotype diversity within dog breeds.  The boxer genome was shown to have homozygosity over 62% of the genome with long blocks having the same haplotype on both chromosomes. The authors looked at the haplotype structure and linkage disequilibrium (LD) across 224 dogs – 10 each from ten breeds and one each from an additional 24 breeds. They used this analysis to construct a population genetics picture of dogs. Among the conclusions is that the dog genome is older (9,000 generations) than the human genome (4,000 generations).   

This is probably a good spot to briefly discuss homozygosity and why that is important.  In terms of experiments. It reduces interindividual variation based on genetics.  Laboratory rats for example have nearly identical genomes after 20 crosses (sib-sib, parent-offspring).  There is a previous post on this blog that discusses stochastics based on behavioral variation in rats with nearly identical genotypes. Dog breeding is a variation on that theme. Dogs do not have the same high degree of homozygosity but they are in the intermediate range.  The majority of dogs in the US are not pure bred but are of mixed heritage.  They can still inherit morphological and behavioral traits as well as genetically based diseases.   The human genome has a lower level of homozygosity due to widespread migration from a common ancestor about 150,000 years ago, a longer life span, as well as cultural constraints such as limits on consanguinity or marriage or a reproductive relationship between two closely related individuals. In the case of marriage by first cousins there is data on consanguinity rates between countries. The medical concern with this practice is that as homozygosity increased the risk of genetically determined autosomal recessive illness increases. Autosomal dominant conditions remain problematic but are not contingent on inheriting identical genes from both parents.   

Species	Homozygosity - same alleles inherited from each biological parent
Norwegian Rat Rattus norvegicus	1: Considered genetically identical at 20 generations of crossbreeding but some heterozygous alleles can be found out to 40 generations. (7) 2:  Rat breeds (phenotypes) are analogous to dog breeds – as an example the albino lab rat is still Rattus norvegicus. 3:  Experimental results on one inbred colony cannot be generalized to the next.
Domestic dogs Canis familiarus	1:  Degree of homozygosity varies with breed and specifics of breeding procedure for pure bred dogs.  Pure bred dogs – 63% homozygosity (10) Mixed breed dogs – 53% homozygosity (10)
Humans Homo sapiens	1: 11% homozygosity in individuals who parents were first cousins (consanguineous) compared with the expected value of 1 out of 16 or 6% (8) applying basic models 2:   Range of homozygosity in humans is wide based on evolutionary factors (bottlenecks, founder effects, inbreeding, outbreeding, background relatedness).  Runs of homozygosity (ROH) are studied more often than whole genome comparisons.

 

In summary, the genetics of domestic dogs is interesting just considering the phenotypic diversity of Canis familiarus.  It highlights issues of classification and that have been discussed in many places on this blog. Students of biology are familiar with these issues from practically every course they have ever taken.  That does not appear to be the case for people who never studied these problems.  Medicine and psychiatry as branches of biology have similar degrees of freedom on an individual basis and for classification purposes.  Any physician knows that no two persons with the same diagnosis are identical and yet there are scores of critics, administrators, politicians, and healthcare companies operating under that illusion. There are similar illusions about social constructs describing some subpopulations.  All humans are still Homo sapiens.  Further subclassification at the genomic or molecular level may be possible but it does not negate the meaning of the Linnean classification.  

In terms of temperament, personality, and behavioral characteristics correlations exist at the genetic level.  Since most of the behavioral traits are polygenic in nature – they have to be considered very early results.   

 There are probably as many advocates that claim a diagnosis has a simplified meaning that they are either advocating for or against.  Socially constructed classifications like race are more problematic.  The basic observation that hundreds of obviously different looking dogs belonging to the same genus and species may drive the phenotypic diversity point home.  The fact that these dogs breeds are also morphologically and behaviorally diverse as well as the fact that that develop unique diseases – provides a potential opportunity for studying morphology and disease mechanisms in humans. Despite suggestions about dog being potential models for human neuropsychiatric disorders that may be too strong of an association.  The research I did for this post was interesting from an evolutionary and genomic standpoint.  It highlights potential genetic and neurobiological effects of domestication as a selective breeding process.

Considering the application of a similar phenotypical diversity concept to complex diseases – why would we not expect hundreds of phenotypes?  Current analyses seem to suggest very simple phenotyping.  In the case of major depression – a single item from a rating scale – emotional blunting or anhedonia and genetic correlates. Other complex diseases like asthma, systemic lupus erythematosus, and diabetes mellitus have similar problems.  On the other hand, we can look at the combinatorics of the verbal descriptions of depression and how many of those combination exist in a clinical population and find 126 subtypes of depression. The question for me is why a handful of rating scale phenotypes of depression would exist and not 126 or more? The same is true for any psychiatric disorder. And of those 126 or more types – what is happening at the genetic and molecular levels?  The idea of a better classification based on some verbal hierarchy or rearranging the verbal descriptions does not seem promising to me.  The dilemma of trying to classify natural phenomena by words is always a limitation. There is no better example than biological classification.       

 

George Dawson, MD, DFAPA

 

 

Graphics Credit:  From reference 1 with permission - Copyright Clearance Center License Number 6004620929064

 

References:

1:  Lindblad-Toh K, Wade CM, Mikkelsen TS, et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature. 2005 Dec 8;438(7069):803-19. doi: 10.1038/nature04338.

2:  Bergström A, Stanton DWG, Taron UH, et al. Grey wolf genomic history reveals a dual ancestry of dogs. Nature. 2022 Jul;607(7918):313-320. doi: 10.1038/s41586-022-04824-9. Epub 2022 Jun 29. PMID: 35768506; PMCID: PMC9279150.

3:  Spady TC, Ostrander EA. Canine behavioral genetics: pointing out the phenotypes and herding up the genes. Am J Hum Genet. 2008 Jan;82(1):10-8. doi: 10.1016/j.ajhg.2007.12.001.

4:  Parker HG. Genomic analyses of modern dog breeds. Mamm Genome. 2012 Feb;23(1-2):19-27. doi: 10.1007/s00335-011-9387-6. Epub 2012 Jan 10. PMID: 22231497; PMCID: PMC3559126.

5:  Hecht EE, Kukekova AV, Gutman DA, Acland GM, Preuss TM, Trut LN. Neuromorphological Changes following Selection for Tameness and Aggression in the Russian Farm-Fox experiment. J Neurosci. 2021 Jul 14;41(28):6144-6156. doi: 10.1523/JNEUROSCI.3114-20.2021.

6:  Rahim NG, Harismendy O, Topol EJ, Frazer KA. Genetic determinants of phenotypic diversity in humans. Genome Biol. 2008 Apr 24;9(4):215. doi: 10.1186/gb-2008-9-4-215. PMID: 18439327; PMCID: PMC2643926.

7:  National Research Council (US) International Committee of the Institute for Laboratory Animal Research. Microbial and Phenotypic Definition of Rats and Mice: Proceedings of the 1998 US/Japan Conference. Washington (DC): National Academies Press (US); 1999. Genetic and Phenotypic Definition of Laboratory Mice and Rats / What Constitutes an Acceptable Genetic-Phenotypic Definition. Available from: https://www.ncbi.nlm.nih.gov/books/NBK224550/

8:  Woods CG, Cox J, Springell K, Hampshire DJ, Mohamed MD, McKibbin M, Stern R, Raymond FL, Sandford R, Malik Sharif S, Karbani G, Ahmed M, Bond J, Clayton D, Inglehearn CF. Quantification of homozygosity in consanguineous individuals with autosomal recessive disease. Am J Hum Genet. 2006 May;78(5):889-896. doi: 10.1086/503875. Epub 2006 Mar 21. PMID: 16642444; PMCID: PMC1474039.

9:  Bell JS.  Genetic diversity.  Accessed on March 24, 2025 https://www.akcchf.org/assets/files/Genetic-Diversity_Bell-2021.pdf

10:  Pemberton TJ, Absher D, Feldman MW, Myers RM, Rosenberg NA, Li JZ. Genomic patterns of homozygosity in worldwide human populations. Am J Hum Genet. 2012 Aug 10;91(2):275-92. doi: 10.1016/j.ajhg.2012.06.014. PMID: 22883143; PMCID: PMC3415543.

11:  Shearin AL, Ostrander EA. Leading the way: canine models of genomics and disease. Dis Model Mech. 2010 Jan-Feb;3(1-2):27-34. doi: 10.1242/dmm.004358. PMID: 20075379; PMCID: PMC4068608.

12:  Amfim A, Bercea LC, Cucu N. Canine Genetics and Epidemiology of Behavior in Dogs. Epizootics-Outbreaks of Animal Disease: Outbreaks of Animal Disease. 2025 Feb 5:105.

13:  Ilska J, Haskell MJ, Blott SC, Sánchez-Molano E, Polgar Z, Lofgren SE, Clements DN, Wiener P. Genetic Characterization of Dog Personality Traits. Genetics. 2017 Jun;206(2):1101-1111. doi: 10.1534/genetics.116.192674. Epub 2017 Apr 10. PMID: 28396505; PMCID: PMC5487251.

14:  Friedrich J, Strandberg E, Arvelius P, Sánchez-Molano E, Pong-Wong R, Hickey JM, Haskell MJ, Wiener P. Genetic dissection of complex behaviour traits in German Shepherd dogs. Heredity (Edinb). 2019 Dec;123(6):746-758. doi: 10.1038/s41437-019-0275-2. Epub 2019 Oct 14. PMID: 31611599; PMCID: PMC6834583.

15:  Handegård KW, Storengen LM, Joergensen D, Lingaas F. Genomic analysis of firework fear and noise reactivity in standard poodles. Canine Med Genet. 2023 Mar 8;10(1):2. doi: 10.1186/s40575-023-00125-0. PMID: 36890545; PMCID: PMC9996964.

16: Boyko AR, Quignon P, Li L, Schoenebeck JJ, Degenhardt JD, Lohmueller KE, Zhao K, Brisbin A, Parker HG, Vonholdt BM, Cargill M. A simple genetic architecture underlies morphological variation in dogs. PLoS biology. 2010 Aug 10;8(8):e1000451.

17:  Morrill K, Chen F, Karlsson E. Comparative neurogenetics of dog behavior complements efforts towards human neuropsychiatric genetics. Human Genetics. 2023 Aug;142(8):1231-46.

18. H. J. Noh et al., Integrating evolutionary and regulatory information with a multispecies approach implicates genes and pathways in obsessive-compulsive disorder. Nat. Commun. 8, 774 (2017). doi: 10.1038/s41467-017-00831-x; pmid: 29042551

19. N. H. Dodman et al., A canine chromosome 7 locus confers compulsive disorder susceptibility. Mol. Psychiatry 15, 8–10(2010). doi: 10.1038/mp.2009.111; pmid: 2002940820

20. K. L. Overall, Natural animal models of human psychiatric conditions: Assessment of mechanism and validity. Prog. Neuropsychopharmacol. Biol. Psychiatry 24, 727–776 (2000). doi: 10.1016/S0278-5846(00)00104-4; pmid: 11191711

21:  Callaway E. How ancient humans bred and traded the first domestic dogs. Nature. 2025 Nov 13. doi: 10.1038/d41586-025-03755-5. Epub ahead of print. PMID: 41233576.